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CANCER - Coggle Diagram

- - - - heriditary cancer syndromes- bcc. hedgehog(9q patch)- gorlin's syndrome due to less ptch medulloblastome
    - - mutations in S cells-> p53 and gtpase ras. Squamous cells are present also in lungs and colon. COX 2 inhibitors not promising(5*heart attacks)
    - - Basal layer of Dermis
        
        MAPK pathway- grb2 and sos activaiton-> sos activates ras-> ras gtp to b raf-> activates mek. B(RAF) mutations-> single sub(val-glu)-> acts as a monomer
        
        Vemurafenib- inihibitor of Braf-> cell cycle arrest+apotosis(reemerged)
        
        deletion of exons(4-8) yeild p61 braf(v600e)-> lacks ras binding domain ( forms dimers resisting drug)
        
        Trametinib inhibits mek(allosteric), combined therapies are beneficial -> colorectal
  - - - Xermatosa Pigmentosum- prone to UV light mutations
- - - - Most common TSG-> p53(haults cell cycle to cause dna repair), maintains integrity
  - - - -hyperactivation og EGFR-> resist cell death, sustaing prolif, evade growth suppressors
        
        RTK
        
        1) RTK mutation-> indep of ligand binding
        
        2) RTK is amplified
        
        3) Chromosomal rearrangements- fusion protiens-> hyperactivations
        
        4) Duplication of kinase domain-> ligand indep
        
        5) Autocrine signalling of ligands
        
        point mutations, localized duplication, chromosomal translocation(control of a diff promoter)
  - - - 1) Sonic hh- limb,eye and brain
        
        hh present, receive, no. Lack of it causes homopresencephaly
        
        Usuually switched off in adults, but needed in stem cell maintanaince and tissue regeneration
      - 2) Indian hh- bone(chondrocyte)
      - 3) Desert hh- reproductive tissues, schwanncells(sheath). lack of it-> sex reverse
    - - CILIUM
        
        Its a extention of microtubules from PM. form at g1 and resorb before mitosis. IFT(Intra flagellar transport).
        
        Kinesin(travel up), Dynein(go down)
    - - N terminus of hh i added with palmitate(hhat).
      - When its on, ptch(gpcr) receptor is endocytosed along with ligand. GLI-FL dissociates from SUFU
    - - feedback signalling- gli, ptch1, hip1
      - prolif- myc, cyclin,
      - migration and invasion- snai1, jag2
      - Angiogenesis- vegf
      - SC regen- fst1, grem1, bmp4
      - type 1-4 mechanisms
        
        1)lof in ptch or gof in smo(ligand indep)
        
        2) autocrine activation(lig dep)
        
        3) paracrine activation by tumour cells (dep)
        
        4) auto/para aberrant activation
    - - Purkinje cells release hh to granular cells-> proliferation during post natal life(p5-p10). GCP then becomes unresponsive to hh, migrates from egl to igl to differentiate to neurons-> output in cerebellum.
        
        During damage to brain-> astrocytes are acitvated (producing shh) neurons ,cell prolif and (glia, endothelial cells).
      - MEDULLOBLASTOMA- most common malignant brain tumour in children. symp-> tiredness, trouble walking, due to lof in ptch( ligand indep)
        
        individuals born with 1 mutant of patch will get 2, hyperactive hh signaliing. or we have smo gof mutant( smo2 oncogenic form- localised to cilia even when ligand is absent. ( leu553trp)-> skeletal mucscle cancer.
        
        alteration in camp -> mb
        -18% taget mycn gene
        -several non coding rna
        
        TREATMENT OPTIONS
        
        -agressive surgery, craniospinal radiotherapy, chemotherapy-> results in intellectual+hormonal issues. Those with recurrent disease have poor prognosis.
        
        smo inhibitors -> gdc-0449/vismodegib-> for metastatic bcc and recurrent. localised-> cant be targetted by surgery or radiotherapy.but is of concern in prepubescent people -> since hh is important in skeletal neural growth.
        
        gdc-0049-. orally available inhibitor of smo
        
        NGS+ bioinformatic- novel pathways for advanced treatments, dual pathway inhibitors, role of non coding in tumour heterogenetiy
        
        RESISTANCE TO HH PATHWAY TREATMENTS
        
        impaired inhibitor, smo binding pocket_ impaired)
        
        depletion of SUFU
        
        upregulate gli2
        
        upregulate target genes
        
        gli1 activation indep of smo-> non canonical
        
        through ras/mek/pi3k/tgf-b
        
        OTHER THERAPIES
        
        CHEMOTHERAPY- depends on location, grade of tumour, condition of patient. But not selective(targets all dividing cells)
        
        adjuvant chemotherapy- provided after surgery to destroy micro metastasis
        
        neo-adjuvant- before surgery to reduce volume
        
        cytotoxic drugs that are not phase specific. alkylating agents(non specific). Taxanes and vinka alkaloids target cells in M phase..PARP inhibitor and antimetabolites target cells in S phas
        
        DRUG CATEGORIES
        
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        MONOCLONAL ANTIBODIES- o(full mouse), xi(variable-mouse), zu(only tip mouse variable), u(fully human).
        
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        radiotherapy- 30% cured, effective if beningn
        
        TARGETTED THERAPY FOR CANCER IN GENERAL
        
        small molecule inhibitors(for hh, btk), next gen sequencing, Immunotherapy(mabs, car-t cells, checkpoint therapy, nk cell+dc
        
        TK
        
        Receptor Tyrosine Kinases
        
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        Non-receptor tyrosine Kinases
        
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        MECHANISMS
        
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        Chronic Myeloid Leukemia(CML)- malignant disorder of hsc. Treated with hydroxyurea-> inhibits synthesis of deoxyribonucleotides and inhibits g1/s phase
        
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        CHECKPOINT IMMUNOTHERAPY-cofactor bw dc and t cell
        
        PD-1-> binds to its ligand and cause intracellular signalling-> t cell mediation phosphorylates tyrosine in pd-1 cytoplasmic tail-> ligands bring together two pd-1 molecules(binding of sh2 domains)-> T cell inhibition
        . CTLA4(competes to bind to cd80)-> prevents co stim via cd28 (only has ec domain)
        
        TUMOUR MICROENVIRONMENT- tumours increase pd-l1. pembrolizumab,
        nivolumab bind to pd-1 binding site-> inhibiting recognition of ligand.
        Treatment options depending on location-> glioblas(low icb), skin melanoma(high icb), pancreatic adenocarcinoma(low icb), lung adeno(high icb), renal carc(high icb)
        
        TYPES
        
        1) shh-a (adolescnets)
        
        2) shh-b (babies with poor prognosis)
        
        3) shh-y( good prognosis)
        
        4) shh-omega(adults)
- - - - 1) Initiation-> genetic change- spontaneous mutation, by carcinogenic agent, dysregulation og signalling pathways.
      - 2) Promotion-> epigenetic changes -> lengthy. preneoplastic cells accumulate. growth rate may be affected by chemopreventive agents.
      - 3) Progression- further genetic changes-> metastatic potential
      - DETAILED STEPS- Primary tumour formation, localized invasion, intravasation, circulation-> respiratory, extravasation, micrometstasis, macro
    - - 1) SUSTAINED PROLIFERATIVE SIGNALLING- i)ability to synthesizw growth factors, ii)increase growth factor receptors(her2),iii)truncation of receptor(ligand indep)(lung cancer)
      - 2) EVADING GROWTH SUPPRESSORS- E cadherin contact inhibition-> have a defined boundary(tsg)
      - 3) RESISTING CELL DEATH- p53 expression causes increased cell death(bax)_cyct
      - 4) INDUCING ANGIOGENESIS- VEGF causes bind to endothelial cells. nutrients+o2 needed
      - 5) REPLICATIVE IMMORTALITY- as cells divide telomeres shorten. In cancer cells telomeres do not shorten
      - 6) ACTIVATION OF INVASION AND METASTASIS- mutistep process-> intra,extravasation, growth, EMT, downregulation of E-cadherin, increased cell invasion genes(MMp+Rac